De novo NAD synthesis contributes to CD8 T cell metabolic fitness and antitumor function.

The dysfunction and clonal constriction of tumor-infiltrating CD8 T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8 T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8 T cell metabolic and functional fitness. De novo NAD synthesis is involved in CD8 T cell metabolism and antitumor function. KP-derived NAD promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD synthesis limits CD8 T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD regulates the CD8 T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD synthesis could restore CD8 T cell metabolic fitness and antitumor function.